Herpesviruses are ubiquitous in humans and they have been implicated in diverse malignancies. Human Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus are associated with tumors of lymphoid, epithelial, and endothelial origin in immuno-compromised patients. The oral cavity is a crucial compartment for gamma herpesvirus infection, particularly important for viral replication, transmission and pathogenesis. Employing human oral keratinocytes and lymphatic endothelial cells, we will delineate multiple viral immune evasion mechanisms enabled by regulated protein deamidation, the simplest post-translational modification of proteins. Host innate immunity is the first line of defense and herpesviruses have evolved an array of mechanisms to evade innate immune responses. Studying human KSHV and murine ?HV68, we have uncovered a novel immune evasion mechanism enabled by a family of viral pseudoenzymes and a cellular metabolic glutamine amidotransferase. The viral pseudoenzymes interact with the cellular glutamine amidotransferase and alter its activity to deamidate both cellular and viral proteins, potently evading the interferon induction at multiple steps. Our published and unpublished findings collectively support the conclusion that deamidation is a key mechanism regulating innate immune responses and herpesviruses exploit this mechanism to benefit their infection. In this study, we will investigate how protein deamidation regulates a cytosolic receptor in sensing viral RNA (Aim 1) and the activity of a viral protein in antagonizing interferon induction (Aim 2). Furthermore, we will define the molecular action by which KSHV and ?HV68 deploy vGAT proteins to regulate PFAS in selectively deamidating cellular and viral proteins to evade innate immune detection (Aim 3). Collectively, this study will elucidate a novel mechanism whereby protein deamidation regulates multiple steps of interferon induction, a key innate immune signaling cascade. Our work will establish more general regulatory roles of protein deamidation in fundamental biological processes, such as immune responses. Findings gleaned from this study will advance our understanding in host immune recognition and interferon induction, and potentially guide our future efforts in vaccine design and antiviral therapeutics to treat malignancies associated with human KSHV and EBV.